¹Wayne State University, Detroit, MI, USA
²Mediprobe Research Inc., London, ON, Canada
³Department of Medicine, University of Toronto, Toronto, ON, Canada

Conflicts of interest:
Gita Gupta has no conflicts of interest. Aditya Gupta has been a clinical trials investigator, advisory board member, consultant, and speaker for Valeant. Aditya Gupta was involved in preclinical studies of tavaborole for Anacor Pharmaceuticals Inc. and has consulted for Anacor. Kelly Foley is an employee of Mediprobe Research Inc. which conducts clinical trials under the supervision of Aditya Gupta.

ABSTRACT
Onychomycosis is a stubborn fungal infection of the nails that can be difficult to effectively manage. One of the challenges with topical therapies is penetrating the nail plate to reach the site of infection. As the first antifungal in a boron-containing class of drugs with a novel mechanism of action, tavaborole is able to penetrate the nail plate more effectively than ciclopirox and amorolfine lacquers. In Phase II/III clinical trials, tavaborole was shown to be safe and clinically effective. Tavaborole 5% solution was approved by the US FDA for the treatment of toenail onychomycosis in July 2014 and is an important addition to the topical treatment arsenal against this stubborn infection.

Key Words:
clinical efficacy, dermatophyte, fungal infection, nail penetrance, nondermatophyte, onychomycosis, tavaborole, topical treatment

Introduction

Onychomycosis is a persistent fungal infection of the nails and nail bed, predominantly caused by the dermatophytes Trichophyton
rubrum or Trichophyton mentagrophytes.¹ The prevalence of onychomycosis in Europe and North America ranges from 3.22- 8.9%,^2,3 with recurrence and reinfection occurring in up to 25%⁴. Distal lateral subungual onychomycosis (DLSO) is the most common clinical presentation, invading the nail plate, nail bed, and hyponychium from the distal edge and lateral nail folds.¹

Treatment for onychomycosis consists of systemic (oral) and topical medications, with or without mechanical/chemical debridement. Systemic therapy is generally more successful
than topical therapy with clinical cure rates ranging from 40-80%.⁵ The advantage to systemic therapy is that medication can directly reach the site of infection in the nail bed.⁶ However, systemic therapy may not be feasible for those who are immunocompromised or at risk for drug-drug interactions (e.g., the elderly and/or diabetics).⁷ Alternatively, other patients are uncomfortable with long-term use of oral medications. Oral antifungal medications have been associated with asymptomatic increases in liver enzymes and there is a small risk of hepatotoxic injury.^8,9 Thus, topical therapies have an important role in onychomycosis management.

The efficacy of topical therapy for onychomycosis ranges from 5.5-17.8% for complete cure and 29-55% for mycological cure.¹⁰ The lower efficacy of topical treatments as compared to systemic therapy can be attributed to their limited ability to reach the site of infection.¹¹ In order for topical treatments to be effective, they need to penetrate the nail plate and down into the nail bed, and mechanical or chemical nail debridement of nails may facilitate this. The major advantage to topical therapy is that long-term use is safe, with minimal side effects.¹¹ Additionally, topical treatments used in combination with systemic treatment may increase clinical efficacy. Furthermore, fungal resistance to azole medications has become a concern in recent years.¹² Therefore, there is a need for new topical therapies for onychomycosis.

Tavaborole: A Novel Topical Antifungal

Tavaborole 5% solution (Kerydin^®) was approved by the US FDA for treatment of onychomycosis in July 2014. Tavaborole is the first in a new class of boron atom-containing drugs, the oxaboroles. Tavaborole’s mechanism of action is unique from current antifungals. Other antifungal agents act by blocking ergosterol synthesis (triazoles and terbinafine),⁶ or interfering with microbial metabolism (ciclopirox).¹³ Tavaborole inhibits protein synthesis, and thus fungal cell growth, by binding to leucyl-tRNA synthetase (LeuRS), an aminoacyl-tRNA synthetase (AARS).¹⁴ AARSs are critical for correct DNA translation and contain proofreading editing sites. Tavaborole binds to the editing site of LeuRS, trapping tRNA and preventing further DNA translation and protein synthesis.¹⁴ In vitro studies have shown that tavaborole can inhibit a wide range of fungal species, with minimum inhibitory concentrations (MIC) against dermatophytes, nondermatophyte molds, and yeasts (Table 1)¹⁵ allowing for potential treatment of mixed dermatophyte-nondermatophyte/mold infections. Of note is the potential for tavaborole to act against Fusarium and Malassezia species.¹⁵ Additionally, tavaborole’s low molecular weight compared to other available topical antifungal agents appears to allow for increased nail penetrance, with increased penetrance demonstrated compared to both amorolfine and ciclopirox.^16,17 Tavaborole’s broad spectrum of antifungal activity, coupled with its ability to penetrate the nail plate, suggested that it may be an effective topical treatment for toenail onychomycosis and led to its investigation in Phase I-III clinical trials.

Clinical Efficacy

Phase I
A Phase I study assessed the efficacy of once daily tavaborole 7.5% solution for 28 days in 15 otherwise healthy patients with severe onychomycosis of both great toenails (at least 80% involvement).¹⁸ Additionally, at least one great toenail was potassium hydroxide (KOH) positive, each great toenail had a combined thickness of the nail plate and nail bed of >3 mm, and at least six other toenails were diagnosed with onychomycosis. After 14 and 28 days of treatment, negative culture was reported for 88% (21/24) and 100% (24/24) of toenails, respectively. Clinical improvement was also observed 2-4 months following treatment, with an average clear nail growth of 1.2 mm.¹⁸

Phase II
Three Phase II studies have been conducted to evaluate the efficacy of a range of doses for tavaborole.¹⁹ All of these studies enrolled adult patients (18-65 years of age) with mild to moderate onychomycosis of at least one great toenail (20-60% nail involvement) and did not allow debridement of the nails during treatment. Study 200/200A (N=187) was a double-blind, randomized, vehicle-controlled trial evaluating 2.5%, 5%, and 7.5% tavaborole solution applied to affected toenails once daily for 3 months, followed by three times weekly for 3 months.¹⁹ The primary efficacy endpoint at 6 months was treatment success of the target toenail, defined as an Investigator Static Global Assessment (ISGA) of clear or almost clear plus negative culture or ≥2 mm of new clear nail growth plus negative culture. The rates of treatment success for all tavaborole treatments were significantly greater than vehicle control (P=0.030). While the number of patients that achieved negative culture was higher in tavaborole groups than vehicle, the differences were not statistically significant (Table 2).¹⁹

Studies 201 (N=89) and 203 (N=60) were open-label trials with the same primary efficacy endpoint as Study 200/200A, treatment success.¹⁹ Patients in Study 201 applied tavaborole 5% solution (Cohort 1) or tavaborole 7.5% solution (Cohort 2) to all affected toenails once daily for 6 months. Cohort 3 applied tavaborole 5% solution once daily for 12 months. Patients in Study 203 applied tavaborole 1% once daily for 6 months or tavaborole 5% once daily for 30 days, followed by three times weekly for 5 months. Efficacy outcomes are listed in Table 2.¹⁹ Overall, treatment with tavaborole was very promising and well tolerated, prompting larger-scale Phase III trials to be conducted. The 5% concentration of tavaborole was selected for Phase III testing.

Phase III

Two identical multi-center, randomized, double-blind, vehiclecontrolled clinical trials were conducted (Study 301, N=593 and Study 302, N=601).^20,21 Patients aged 18 years and older with mycologically confirmed (positive KOH and culture) onychomycosis involving 20-60% of the great toenail applied either tavaborole 5% solution or vehicle solution once daily for 48 weeks. At Week 52, complete cure (completely clear nail and mycological cure) and mycological cure (negative KOH and negative culture) were assessed (Table 3). ^20,21 Treatment with tavaborole 5% solution led to a significantly greater complete cure and mycological cure rates than vehicle treatment in both clinical trials (Ps≤0.001). Additionally, the outcome of completely or almost completely clear nail (≤10% nail involvement) plus negative mycology was significantly greater with tavaborole 5% solution compared to vehicle (Study 301: 15.3% vs. 1.5%; Study 302: 17.9% vs. 3.9%, P≤0.001).^20,21

Adverse Events

For all three Phase II studies combined, treatment-emergent adverse events (TEAEs) occurred in 177 of 366 patients.¹⁹ There were 13 reports of serious adverse events (AEs), unrelated to treatment. A reduction in dosing frequency and/or treatment discontinuation resolved any mild to moderate application site reactions. Specifically, in Study 200/200A, four patients in the tavaborole 7.5% solution group required ‘drug holidays’ (discontinued treatment until persistent grade 2 stinging/burning, pruritus, or grade ≥3 irritation was resolved, then treatment resumed with reduced frequency), while no patients in the tavaborole 5% solution group required a break from treatment. Other TEAEs reported included influenza (9.0%), pharyngitis (3.8%), upper respiratory tract infection (3.6%), tinea pedis (3.8%), headache (3.6%), contact dermatitis (2.5%), onychomadesis (1.4%), and tooth extraction (0.8%).¹⁹

Safety data was available for 1186 participants in the Phase III clinical trials.²⁰ No serious AEs were considered treatment related. In both trials, discontinuation due to treatment was comparable for tavaborole 5% solution and vehicle groups. TEAEs in ≥1% of participants treated with tavaborole were limited to application site reactions (exfoliation 2.7%, erythema 1.6%, and dermatitis 1.3%), and there were few reports of TEAE’s due to vehicle (exfoliation 0.3%, erythema and dermatitis 0%).20,21 Taken together, these results demonstrate that tavaborole 5% solution is both safe and more effective than vehicle in treating toenail onychomycosis.

Discussion

Tavaborole 5% solution was approved by the US FDA in July 2014 for use as a topical treatment for onychomycosis. Phase III clinical trials demonstrated that once daily use of tavaborole 5% solution for 48 weeks produced significantly higher rates of mycological and complete cure than vehicle.^20,21 Adverse events reported from Phase II and III trials indicate that the 5% formulation of tavaborole provides optimum efficacy and safety, producing mild application site reactions in a small number of patients.^19-21 As with all topical treatments for toenail onychomycosis, treatment outcomes are, in part, reliant on patient compliance and commitment to therapy, as toenails generally require at least 10-12 months to regrow.

Formulating an agent capable of penetrating the nail plate is one of the major challenges in developing topical treatments for onychomycosis. Tavaborole’s low molecular weight and high solubility allow for greater nail penetration and subsequent delivery of medication to the nail bed. The ability of tavaborole to effectively penetrate the nail plate prevents the need for mechanical debridement that may be required with other topical treatments. Additionally, tavaborole 5% solution’s broad-spectrum antifungal activity against dermatophytes, nondermatophytes, and yeasts make it a potential treatment for mixed infections. This is a relevant concern as little is known about the efficacy of current treatments for mixed infections, which may also contribute to the high recurrence rates observed in onychomycosis.

The availability of tavaborole 5% solution for the topical management of toenail onychomycosis may represent the promising start of a new line of treatments with increased nail penetrance and a novel mechanism of action against pathogenic fungi.

References

1. Welsh O, Vera-Cabrera L, Welsh E. Onychomycosis. Clin Dermatol. 2010 Mar 4;28(2):151-9.
2. Gupta AK, Daigle D, Foley KA. The prevalence of culture-confirmed toenail onychomycosis in at-risk patient populations. J Eur Acad Dermatol Venereol. 2015 Jun;29(6):1039-44.
3. Sigurgeirsson B, Baran R. The prevalence of onychomycosis in the global population: a literature study. J Eur Acad Dermatol Venereol. 2014 Nov;28(11):1480-91.
4. Scher RK, Baran R. Onychomycosis in clinical practice: factors contributing to recurrence. Br J Dermatol. 2003 Sep;149 Suppl 65:5-9.
5. de Sa DC, Lamas AP, Tosti A. Oral therapy for onychomycosis: an evidencebased review. Am J Clin Dermatol. 2014 Feb;15(1):17-36.
6. Elewski BE. Mechanisms of action of systemic antifungal agents. J Am Acad Dermatol. 1993 May;28(5 Pt 1):S28-S34.
7. Baran R, Hay RJ, Garduno JI. Review of antifungal therapy, part II: treatment rationale, including specific patient populations. J Dermatolog Treat. 2008 19(3):168-75.
8. Garcia Rodriguez LA, Duque A, Castellsague J, et al. A cohort study on the risk of acute liver injury among users of ketoconazole and other antifungal drugs. Br J Clin Pharmacol. 1999 Dec;48(6):847-52.
9. Kao WY, Su CW, Huang YS, et al. Risk of oral antifungal agent-induced liver injury in Taiwanese. Br J Clin Pharmacol. 2014 Jan;77(1):180-9.
10. Gupta AK, Daigle D, Foley KA. Topical therapy for toenail onychomycosis: an evidence-based review. Am J Clin Dermatol. 2014 Dec;15(6):489-502.
11. Murdan S. Enhancing the nail permeability of topically applied drugs. Expert Opin Drug Deliv. 2008 Nov;5(11):1267-82.
12. . Parker JE, Warrilow AG, Price CL, et al. Resistance to antifungals that target CYP51. J Chem Biol. 2014 Oct;7(4):143-61.
13. Gupta AK, Ryder JE, Baran R. The use of topical therapies to treat onychomycosis. Dermatol Clin. 2003 Jul;21(3):481-9
14. Rock FL, Mao W, Yaremchuk A, et al. An antifungal agent inhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site. Science. 2007 Jun 22;316(5832):1759-61.
15. Sanders V, Baker SJ, Alley MRK, et al. Microbiological activity of AN2690, a new antifungal agent in development for the topical treatment of onychomycosis. [Poster P1608]. Presented at the 64th Annual Meeting of the American Academy of Dermatology; March 3-7, 2006; San Francisco, CA.
16. Elewski BE, Tosti A. Tavaborole for the treatment of onychomycosis. Expert Opin Pharmacother. 2014 Jul;15(10):1439-48.
17. Hui X, Baker SJ, Wester RC, et al. In vitro penetration of a novel oxaborole antifungal (AN2690) into the human nail plate. J Pharm Sci. 2007 Oct;96(10):2622-31.
18. Beutner KR, Sanders V, Hold K, et al. An open-label, multi-dose study of the absorption and systemic pharmacokinetics of AN2690 applied as a 7.5% solution to all toenails of adult patients with moderate to severe onychomycosis. [Poster 1823]. Presented at the 65th Annual Meeting of the American Academy of Dermatology; February 2-6, 2007; Washington, DC.
19. Toledo-Bahena ME, Bucko A, Ocampo-Candiani J, et al. The efficacy and safety of tavaborole, a novel, boron-based pharmaceutical agent: phase 2 studies conducted for the topical treatment of toenail onychomycosis. J Drugs Dermatol. 2014 Sep;13(9):1124-32.
20. Elewski BE, Aly R, Baldwin SL, et al. Efficacy and safety of tavaborole topical solution, 5%, a novel boron-based antifungal agent, for the treatment of toenail onychomycosis: results from 2 randomized phase-III studies. J Am Acad Dermatol. 2015 Jul;73(1):62-9.
21. Kerydin^™ (tavaborole) topical solution, 5% [Full prescribing information]. Palo Alto, CA: Anacor Pharmaceuticals, Inc.; revised July 2014. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204427s000lbl.pdf. Accessed September 20, 2015.
22. Jo Siu WJ, Tatsumi Y, Senda H, et al. Comparison of in vitro antifungal activities of efinaconazole and currently available antifungal agents against a variety of pathogenic fungi associated with onychomycosis. Antimicrob Agents Chemother. 2013 Apr;57(4):1610-6.

¹Division of Dermatology, Department of Medicine, University of Toronto, Toronto, ON, Canada
²Mediprobe Research Inc., London, ON, Canada

Conflict of interest:
None reported

ABSTRACT
Minoxidil is a Health Canada and US FDA-approved medication for hair loss in men and women. While 5% minoxidil foam has been approved for men since 2006, Health Canada and the FDA only approved 5% minoxidil foam for female pattern hair loss (FPHL) in 2014. Recent Phase III clinical trials demonstrated the efficacy of once daily 5% minoxidil foam for treatment of FPHL, where a significant change from baseline in the target area hair count was observed compared to placebo. Similar changes in hair count for 5% foam and twice daily 2% minoxidil solution established noninferiority of the 5% foam formulation. Five percent minoxidil foam provides an additional option for women with FPHL and will soon be available in Canada.

Key Words:
androgenetic alopecia, AGA, female pattern hair loss, FPHL, 5% minoxidil foam, hair loss, treatment, clinical efficacy

Introduction

Female pattern hair loss (FPHL), also known as androgenetic alopecia (AGA), is one of the most common forms of alopecia in women. Onset of hair loss can occur as early as one’s 20s and affect as many as 40% of Caucasian women over the age of 70 years.^1,2 FPHL can be a source of social distress and greatly impair quality of life.³ There are a variety of treatments for FPHL including antiandrogen medications, topical treatments, laser/light devices, and hair transplantation,⁴ with choice of treatment depending on the extent of hair loss, patient health, cost, and preference. The goal of treatment is to slow hair loss and potentially increase hair growth; however, treatment is not always successful.

Until recently, the only US FDA-approved medication for women was 2% minoxidil solution, while both the 2% and 5% solutions are available for men. Minoxidil may stimulate hair growth by increasing the anagen phase of the hair cycle, but the exact mechanisms are currently unknown.⁵ In 2006, the FDA approved 5% minoxidil foam for the treatment of androgenetic alopecia in men after clinical testing showed that it increased hair growth after 48 weeks of twice daily use.^6,7 Additionally, the incidence of pruritus in men was lower with the 5% foam than the 5% solution, likely due to propylene glycol in the solution formulation.^6,7 Because of its efficacy in treating male hair loss, 5% minoxidil became a viable option for women suffering from FPHL. Clinical trial results in women suggest that 5% minoxidil foam is an effective treatment for FPHL, leading to its Health Canada and FDA approvals for this indication in 2014.⁸

Past Clinical Evidence

In Phase III clinical trials, both the 5% and 2% minoxidil formulations have demonstrated similar efficacy in promoting hair growth in women with hair thinning over the frontoparietal scalp. Lucky et al. conducted a 48-week randomized, doubleblind, placebo controlled trial that assessed target area hair count (TAHC) following twice daily application of 5% minoxidil solution, 2% minoxidil solution, or 5% solution vehicle in women with frontoparietal hair loss that could be accompanied with, or without, frontal hairline recession.⁹ Patient and investigator assessments of hair growth and scalp coverage were performed in addition to TAHC. Both the 5% and 2% minoxidil solutions showed significantly higher TAHCs compared to placebo (P < 0.001, Table 1). The investigator assessments followed the same pattern as the TAHC results; however, patient-reported assessment of hair growth was significantly greater in the 5% minoxidil solution group than the 2% minoxidil solution or vehicle groups.⁹

The efficacy of once daily application of 5% minoxidil foam against 2% minoxidil solution in the treatment of frontoparietal hair loss in women was investigated in a randomized, singleblind Phase III trial.¹⁰ Change in non-vellus hair count and width, blind evaluator and patient review of photographs, and patient assessment of product aesthetics and benefits were assessed after 24 weeks of use. Five percent minoxidil foam applied once daily was shown to be noninferior to twice daily 2% minoxidil solution, as measured by change in non-vellus hair count (Table 2) and hair width. Women in the 5% foam group agreed more strongly that treatment did not interfere with grooming routines than did women in the 2% solution group (P = 0.002).¹⁰ In separate studies, both the twice daily use of 5% minoxidil solution and once daily use of 5% minoxidil foam were shown to be noninferior compared to twice daily use of 2% minoxidil solution.

Recent Clinical Trials

Two randomized, double-blind, parallel, international multicenter Phase III trials of 5% minoxidil foam were recently completed. Both trials assessed the efficacy of once daily use of 5% minoxidil foam in female participants aged 18 years and older.^11,12 In the first trial, participants were assigned to once a day treatment with 5% minoxidil foam or vehicle foam for 24 weeks (minoxidil: n=203, vehicle: n=201).¹¹ Efficacy was assessed at weeks 12 and 24 and safety and adverse events were monitored every 6 weeks. At weeks 12 and 24, changes in TAHC from baseline were significantly higher in the minoxidil-treated group than the vehicle-treated group (P < 0.0001, Table 2). Also at 24 weeks, patient-reported assessment of scalp coverage was determined to be significantly higher with minoxidil treatment compared to vehicle (P < 0.0001).¹¹

Participants in the second trial were assigned to once a day treatment with 5% minoxidil foam or 2% minoxidil solution twice daily for 52 weeks (n=161 in each group).¹² TAHC was assessed at weeks 12, 24, and 52 and safety and adverse events were monitored regularly. The change in TAHC from baseline in the 5% minoxidil group was shown to be similar to that of the 2% topical minoxidil solution group at weeks 12 (P < 0.4158) and 24 (P = 0.9170, Table 2), as well as at week 52 (P = 0.5980).¹²

Adverse Events

Five percent minoxidil foam was well tolerated in each of the recent clinical trials. The number of participants reporting adverse events after using 5% minoxidil foam was similar to that of participants who used 2% minoxidil solution or vehicle. The most common adverse events reported in at least 2% of participants included weight gain, headache, pruritus, and nasal and upper respiratory tract infections.^11,12 These are similar to the adverse events reported previously by Lucky et al. and Blume- Peytavi et al., who also reported dermatitis, dandruff, erythema, and burning/stinging in both 5% and 2% minoxidil treatment groups.^9,10 Additionally, 5% foam may encourage greater compliance, as Blume-Peytavi et al. reported that pruritus and dandruff occurred significantly less with application of 5% foam than with the 2% solution.¹⁰

Hypertrichosis is a well-known concern among women using hair growth products. While hypertrichosis has been reported with the use of 5% minoxidil,^9,10,13 unwanted growth in sideburn areas was significantly less with 5% foam than with the 2% solution.¹⁰ Advice to women to further limit hypertrichosis includes application of the medication 2-4 hours prior to bedtime and hand washing immediately after application;⁸ however, the presence of hirsutism or hypersensitivity may increase susceptibility to unwanted hair growth that is beyond physician and patient control.^13,14

Six participants in the 5% minoxidil group reported serious adverse events (SAEs) in the placebo controlled trial (1 incidence each of cardiac disorder, gastritis, dehydration, osteoarthritis, ovarian neoplasm, uterine leiomyoma, renal failure, and hypertensive crisis) in comparison to 4 participants in the vehicle group (1 incidence each of fatigue, ovarian cancer, memory impairment, mental status changes, and PTSD; 2 incidences each of cardiac disorder and asthenia).¹¹ In the comparative trial, 2 participants treated with 5% minoxidil reported SAEs (wrist fracture and anxiety) in comparison to 8 participants in the 2% minoxidil group (1 incidence each of angina pectoris, abdominal pain, bile duct stone, anal abscess, influenza, metastatic neoplasm, menometrorrhagia, and asthma).¹² The SAEs are not considered to be clinically relevant to the drug.

Discussion

Recent clinical trials of 5% minoxidil foam for the treatment of FPHL have demonstrated it to be safe and effective, with hair growth outcomes similar to that of the traditional 2% minoxidil solution.^11,12 Phase III clinical trials demonstrated that hair growth with once daily use of 5% minoxidil foam is noninferior to twice daily use of 2% minoxidil solution in women with frontoparietal hair loss.^10,12 Patient-reported improvement in hair volume and coverage appears to be greater with 5% minoxidil foam and once daily application does not substantially interfere with grooming routines.¹⁰ Adverse events may occur with both 5% foam and 2% solution, but these rarely lead to discontinued use. Susceptibility to hypertrichosis may be individual-specific, and should be discussed with patients as a possible side-effect of minoxidil use.

It is suggested that 5% minoxidil be applied for 3-6 months before noticeable improvement can be observed.⁸ While the results of clinical trials demonstrate a statistically significant increase in the total hair count, sometimes these results may fall short of patient expectations; therefore, patients need to be informed that individual results may vary even after 6-12 months of therapy.^4,16 Recent evidence demonstrates that a sulfotransferase enzyme test can successfully identify non-responders to minoxidil.¹⁷ To our knowledge, this test is not commercially available. In addition, some patients may experience an increase in hair shedding, or at least continued hair loss, for the first few months and should be counselled accordingly.^4,16 When women experience improvement in hair growth, continued treatment is required or else improvement will likely be lost and hair loss will revert back to its natural course.^4,18

Five percent minoxidil foam, applied only once daily, has the potential for milder side effects, improved compliance, and greater patient satisfaction with treatment. Indeed, the use of minoxidil as a treatment for FPHL has been shown to improve women’s quality of life.³ Additionally, 5% minoxidil foam provides an alternative option for women who do not wish to use, or who are unable to use, oral anti-androgen or hormonal contraceptive medications as hair loss treatments. The recent approval and availability of 5% minoxidil foam in Canada provides a safe and effective treatment for women with FPHL.

References

1. Blumeyer A, Tosti A, Messenger A, et al. Evidence-based (S3) guideline for the treatment of androgenetic alopecia in women and in men. J Dtsch Dermatol Ges. 2011 Oct;9 Suppl 6:S1-57.
2. Norwood OT. Incidence of female androgenetic alopecia (female pattern alopecia). Dermatol Surg. 2001 Jan;27(1):53-4.
3. Zhuang XS, Zheng YY, Xu JJ, et al. Quality of life in women with female pattern hair loss and the impact of topical minoxidil treatment on quality of life in these patients. Exp Ther Med. 2013 Aug;6(2):542-6.
4. Herskovitz I, Tosti A. Female pattern hair loss. Int J Endocrinol Metab. 2013 Oct;11(4):e9860.
5. Messenger AG, Rundegren J. Minoxidil: mechanisms of action on hair growth. Br J Dermatol. 2004 Feb;150(2):186-94.
6. Olsen EA, Dunlap FE, Funicella T, et al. A randomized clinical trial of 5% topical minoxidil versus 2% topical minoxidil and placebo in the treatment of androgenetic alopecia in men. J Am Acad Dermatol. 2002 Sep;47(3):377-85.
7. Olsen EA, Whiting D, Bergfeld W, et al. A multicenter, randomized, placebocontrolled, double-blind clinical trial of a novel formulation of 5% minoxidil topical foam versus placebo in the treatment of androgenetic alopecia in men. J Am Acad Dermatol. 2007 Nov;57(5):767-74.
8. Drugs@FDA: FDA Approved Drug Products. Women’s rogaine 5% minoxidil topical aerosol, approval history and label. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. Accessed September 1, 2014.
9. Lucky AW, Piacquadio DJ, Ditre CM, et al. A randomized, placebo-controlled trial of 5% and 2% topical minoxidil solutions in the treatment of female pattern hair loss. J Am Acad Dermatol. 2004 Apr;50(4):541-53.
10. Blume-Peytavi U, Hillmann K, Dietz E, et al. A randomized, single-blind trial of 5% minoxidil foam once daily versus 2% minoxidil solution twice daily in the treatment of androgenetic alopecia in women. J Am Acad Dermatol. 2011 Dec;65(6):1126-34 e2.
11. Johnson & Johnson Consumer and Personal Products Worldwide. A phase 3 multi-center parallel design clinical trial to compare the efficacy and safety of 5% minoxidil foam vs. vehicle in females for the treatment of female pattern hair loss (androgenetic alopecia). In: ClinicalTrials.gov, Identifier: NCT01226459. Last updated June 3, 2014. Available at: http://clinicaltrials.gov/ct2/show/results/NCT01226459?term=minoxidil&sect=X4301256#othr. Accessed September 1, 2014.
12. Johnson & Johnson Consumer and Personal Products Worldwide. A phase 3 multi-center parallel design clinical trial to compare the efficacy and safety of 5% minoxidil foam vs. 2% minoxidil solution in females for the treatment of female pattern hair loss – androgenetic alopecia. In: ClinicalTrials.gov, Identified: NCT01145625. Last updated May 19, 2014. Available at: http:// clinicaltrials.gov/ct2/show/study/NCT01145625?term=minoxidil&sect=X430126. Accessed September 1, 2014.
13. Dawber RP, Rundegren J. Hypertrichosis in females applying minoxidil topical solution and in normal controls. J Eur Acad Dermatol Venereol. 2003 May;17(3):271-5.
14. Peluso AM, Misciali C, Vincenzi C, et al. Diffuse hypertrichosis during treatment with 5% topical minoxidil. Br J Dermatol. 1997 Jan;136(1):118-20.
15. Hillmann K, Geburtsort K. Results of an investigator-initiated, two-armed, randomized, controlled clinical trial to proof efficacy of a 5% minoxidil topical foam once daily versus a 2% minoxidil solution twice daily on hair volume in women with mild to moderate androgenetic alopecia. Free University of Berlin; 2013. Available at: http://www.diss.fu-berlin.de/diss/receive/FUDISS_thesis_000000095104. Accessed September 1, 2014.
16. Levy LL, Emer JJ. Female pattern alopecia: current perspectives. Int J Womens Health. 2013;5:541-56.
17. Goren A, Shapiro J, Roberts J, et al. Clinical utility and validity of minoxidil response testing in androgenetic alopecia. Dermatol Ther. 2014 Aug 12. [Epub ahead of print]
18. Rogers NE. Medical therapy for female pattern hair loss (FPHL). Hair Transpl Forum Int. 2014;24(3):81,86-8.